The International Epidemiology of Lung Cancer

ORIGINAL ARTICLE
The International Epidemiology of Lung Cancer:

Latest Trends, Disparities, and Tumor Characteristics
Ting-Yuan David Cheng, PhD,a Susanna M. Cramb, PhD,b Peter D. Baade, PhD,b
Danny R. Youlden, BSc,b Chukwumere Nwogu, MD, PhD,c Mary E. Reid, MSPH, PhDd,*
a
Department of Cancer Prevention and Control, Roswell Park Cancer Institutes, Buffalo, New York
b
Cancer Research Centre, Cancer Council Queensland, Brisbane, Queensland, Australia
c
Department of Thoracic Surgery, Roswell Park Cancer Institutes, Buffalo, New York
d
Department of Medicine, Roswell Park Cancer Institutes, Buffalo, New York
Received 13 July 2015; revised 13 May 2016; accepted 26 May 2016

Available online - 27 June 2016
ABSTRACT 2016 International Association for the Study of Lung

Cancer. Published by Elsevier Inc. All rights reserved.
Introduction: Our aim was to update global lung cancer
epidemiology and describe changing trends and disparities.
Keywords: Lung cancer; Epidemiology; Histological type;
Methods: We presented country-specific incidence and Survival; Disparity; International
mortality from GLOBOCAN 2012 by region and socioeco-
nomic factors via the Human Development Index (HDI).
Between- and within-country incidence by histological type
was analyzed by using International Agency for Research on
Introduction
Lung cancer imposes a major disease burden on the
Cancer data on cancer incidence on five continents. Trend
analyses including data from the International Agency for world. Worldwide, lung cancer remains the most com-
Research on Cancer, cancer registries, and the WHO mortality mon cancer diagnosed (excluding keratinocyte carci-
database were conducted using joinpoint regression. Survival noma) and the greatest cause of cancer-related death.
was compared between and within countries and by histo- Lung cancer accounts for 17% and 9% of all cancers in
logical type. men and women, respectively, and represents 19% of all
cancer-related deaths.1 Because of its extraordinary
Results: In 2012, there were 1.82 and 1.59 million new lung disease burden and the international variability in trends
cancer cases and deaths worldwide, respectively. Incidence
for population growth, aging, and smoking behavior, the
was highest in countries with a very high HDI and lowest in
global epidemiology of lung cancer requires continual
countries with a low HDI (42.2 versus 7.9 in 100,000 for
monitoring.
males and 21.8 versus 3.1 in 100,000 for females, respec-
The epidemiology of lung cancer in major developed
tively). In most countries with a very high HDI, as incidence in
countries such as the United States and countries in the
males decreased gradually (ranging from –0.3% in Spain
to –2.5% in the United States each year), incidence in females European Union has consistently been reported.2–5
continued to increase (with the increase ranging from 1.4% However, potential differences in lung cancer rates by
each year in Australia to 6.1% in recent years in Spain). levels of socioeconomic development between countries
Although histological type varied between countries, adeno- have been less well described. This is important because
carcinoma was more common than squamous cell carcinoma,
particularly among females (e.g., in Chinese females, the
adenocarcinoma-to–squamous cell carcinoma ratio was 6.6). *Corresponding author.
Five-year relative survival varied from 2% (Libya) to 30% Disclosure: The authors declare no conflict of interest.
(Japan), with substantial within-country differences. Address for correspondence: Mary E. Reid, MSPH, PhD, Department of
Medicine, Roswell Park Cancer Institutes, Elm and Carlton Streets,
Conclusions: Lung cancer will continue to be a major Buffalo, New York 14263. E-mail: mary.reid@roswellpark.org
health problem well through the first half of this century. ª 2016 International Association for the Study of Lung Cancer.
Published by Elsevier Inc. All rights reserved.
Preventive strategies, particularly tobacco control, tailored
ISSN: 1556-0864
to populations at highest risk are key to reducing the global
http://dx.doi.org/10.1016/j.jtho.2016.05.021
burden of lung cancer.
Journal of Thoracic Oncology Vol. 11 No. 10: 1653-1671

1654 Cheng et al Journal of Thoracic Oncology Vol. 11 No. 10
almost half (49%) of all lung cancer cases now occur in composite index developed by the United Nations
countries ranked as medium to low on the Human Development Program.7 A higher HDI indicates that on
Development Index (HDI),6 a composite measure average, a country’s people live longer, are healthier, are
encompassing population health, knowledge, and living more knowledgeable, and have a better standard of
standards to indicate the development of a country.7 In living than those in countries with a lower HDI.7 Histo-
addition, although some studies have reported within- logical type–specific incidence rates were extracted from
country differences in lung cancer incidence across the online detailed version of Cancer Incidence in Five
defined subpopulations,3,8–10 there is limited under- Continents Volume X.15 Lung cancer was classified into
standing of the overall extent of these geographical dis- two major cell types according to its histological fea-
parities from a global perspective. tures, NSCLC (which includes the subtypes adenocarci-
The histology and molecular markers of lung cancer, noma, squamous cell carcinoma, and large cell
such as genetic mutations, are important when classi- carcinoma) and SCLC, on the basis of the WHO 2004
fying lung cancers for treatment and preventive strate- guidelines.16 A new guideline on histological classifica-
gies.11 For example, widespread temporal increases in tion based on genetic as well as clinical and histological
rates of adenocarcinoma may be explained by changes in features was recently released by WHO.17 As the new
cigarette components and delivery systems,12 as well as guideline is yet to be implemented by cancer registries,
by non–tobacco-related risk factors.13 Overall, the global the classifications used here were based on the 2004
epidemiology of these characteristics in relation to lung definitions.16 Registries were included only if at least
cancer incidence and mortality has yet to be extensively 60% of cases had been microscopically verified.
documented. To examine incidence trends over time, longitudinal
The objectives of this study are to (1) describe the lung cancer data were obtained from IARC18 and indi-
most recent patterns at the country level by region and vidual cancer registries.19–25 Countries were included if
HDI and trends in lung cancer epidemiology worldwide at least 15 years of data were readily available and if, for
as an update of a previous article in this journal pre- IARC data, at least 60% of lung cancer cases were
senting GLOBOCAN 2002 data14; (2) review and discuss microscopically verified and less than 30% were diag-
the global perspectives of the histological and molecular nosed by death certificate. All included countries had
features of lung cancer; (3) report region- and country- more than 100 lung cancers diagnosed in males and fe-
specific profiles, emphasizing disparities and changing males (separately) each year.
trends; and (4) outline opportunities to reduce the Mortality trends over time utilized the WHO Mortality
burden of lung cancer through prevention, early diag- Database.26 This database contains medically certified
nosis, and new therapies, as Discussion. In objective 3, deaths only, so completeness can vary between countries.
we present specific results for African countries, Central Countries were selected on the basis of data availability
and South American countries, Australia, China, and the (at least 12 years of data), the number of deaths each year
United States to elucidate different strategies for pre- (>100 for each sex), and data completeness (>85%).
venting and controlling lung cancer in these populations. China was additionally included as it represents almost
one-fifth of the world’s population, even though the
Methods available mortality data covered less than 10% of China’s
Data population and provided an estimated data completeness
Lung cancer was defined as International Classifica- across the whole country of only 4%.
tion of Diseases (ICD), 10th Revision/ICD-O3 codes C33 In addition, we presented data from the literature on
and C34 and ICD-9 code 162, which include malignant lung cancer epidemiology for China and for African and
neoplasms of the trachea, bronchus, and lung. Data on Central and South American countries because of inad-
lung cancer incidence and mortality were extracted from equate coverage of the national population by the
GLOBOCAN 2012, an International Agency for Research available registries in many of these countries.27,28
on Cancer (IARC) project providing contemporary na-
tional estimates of cancer statistics for 184 countries.6 Statistical Analysis
We present regional incidence and mortality data ac- Incidence and mortality rates were directly age-
cording to geographic area and level of socioeconomic standardized to the World Standard Population as
development, and we provide estimates for specific specified by Segi29 and modified by Doll et al.30 and were
countries selected to be broadly representative of the expressed per 100,000 population. Calculations were
various regions and development levels. Countries are performed in Stata, version 13.1 (StataCorp, College
classified into four levels of development (very high, Station, TX), and trend graphs were created using SAS
high, medium, or low) according to the 2012 HDI, a 9.4 (SAS Institute, Inc., Cary, NC).
October 2016 International Epidemiology of Lung Cancer 1655
Trend analyses were conducted using the Joinpoint males in Eastern Asia (50.4 in 100,000). The highest
Regression Program, version 4.0.4 (National Cancer incidence rates among females were in North America
Institute, Bethesda, MD). The program is designed to (33.8 in 100,000) and Northern Europe (23.7 in
evaluate changing linear trends over time by inserting a 100,000).
joinpoint when the linear trend changes significantly in There have been substantial temporal changes in
either direction or magnitude. All models used the same incidence rates (Fig. 1). The incidence rates for males and
specifications and required a minimum of six data points females in most of the countries classified as having a high
between a joinpoint and either end of the data series and or very high HDI (Australia, Canada, Denmark, Germany,
at least 5 years of data between joinpoints. A maximum the Netherlands, Russia, Sweden, the United Kingdom,
of three joinpoints were allowed. The annual percent and the United States) gradually converged over time.
change was used to report trends. This was due to the significant downward trends among
Age-standardized net survival estimates for lung men and the sustained increase in lung cancer rates in
cancers diagnosed in 2005–2009 and followed up to 31 females, although in the United States incidence has also
December 2009 were obtained from the CONCORD-2 begun to show signs of a decreasing trend among females
study,31 using lung cancer data from 240 registries in since 2010.3,35 In contrast, incidence rates are increasing
60 countries for persons aged 15 to 99 years at diagnosis. in parallel for both sexes in Brazil and Japan and
The Pohar Perme method of estimation was used in this decreasing among both sexes in Hong Kong. Trends in
study to estimate net survival. More recent relative sur- lung cancer incidence rates for the selected countries by
vival estimates were also available by sex for selected sex are listed in Supplementary Table 1.
countries, including Australia (at-risk in 2006–2010, ages Cigarette smoking or tobacco use is the most impor-
0–89 years at diagnosis),34 the United States (at-risk in tant causal risk factor for development of lung cancer. For
2010, ages 0–99 years at diagnosis)33 and the Nordic males and females, smoking causes more than 90% and
countries (diagnosis in 2009–2011, with follow-up to 70% of lung cancer deaths, respectively, in countries with
2012, ages 0–89 years at diagnosis).32 All survival esti- a very high HDI, whereas in countries with a high, median,
mates were calculated under the period method, apart or low HDI, the respective rates are approximately 65%
from NORDCAN, which used the cohort method. Relative among males and 25% among females.36–38 With the
survival estimates by histological features were readily lower smoking prevalence among women, particularly
obtainable from the Surveillance, Epidemiology, and End Asian women (2% in China),39 it is estimated that
Results-18 database (the United States)33 and the approximately half of lung cancers in females worldwide
Australian Cancer Database (Australia).34 are not attributable to primary consumption of combus-
Results are presented in four sections according to tible tobacco for the years 2000 and 2012.40,41
the four stated objectives of this study, with each section The long latency of 30 years between exposure to
incorporating a discussion of their implications for the tobacco smoke and lung cancer development most likely
global burden of lung cancer. explains the delay between lung cancer incidence rates
reflecting preceding smoking prevalence changes.42,43
For example, Hungarian men had the highest lung can-
Results and Discussion cer incidence in Europe in 2012 (76.6 of 100,000),
Recent Patterns and Trends in Lung Cancer reflecting their high smoking prevalence in the late
Epidemiology twentieth century onward (42.7% in 1980).43,44 In
Incidence. In 2012, the world age-adjusted incidence addition, secondhand smoke increases risk for lung
rate of lung cancer was 34.2 in 100,000 for men and 13.6 cancer in nonsmokers,45,46 although its impact on global
in 100,000 for women (Table 1). This translated into lung cancer epidemiology is unclear.
1.82 million new lung cancer cases (in 1.24 million men
and 0.58 million women), which was an increase from Mortality. In 2012, the world age-adjusted mortality
the 2002 estimates (1.35 million for both sexes).14 The rate of lung cancer was 30.0 in 100,000 for men and 11.1
incidence rate was generally highest in socioeconomi- in 100,000 for women (see Table 1). There were 1.59
cally developed countries (very high HDI) and lowest in million deaths attributable to lung cancer, and the
socioeconomically undeveloped countries (low HDI) for number has increased from 1.18 million deaths in
both males and females. However, this effect did not 2002.14 By socioeconomic groupings, the mortality rate
have a consistent gradient, with some countries ranked followed a pattern similar to that of the incidence rates,
as high on the HDI having higher incidence rates than with the highest mortality rate among the countries with
those ranked as very high. With regard to the geographic a very high HDI, followed by countries with a medium
regions, males in Central and Eastern Europe had the HDI, then a high HDI, and finally a low HDI. Among the
highest incidence rate (53.5 in 100,000), followed by geographic regions, males in Central and Eastern Europe
Table 1. Lung Cancer Incidence and Mortality by Region and Selected Countries, 2012
Males Females
Incidence Mortality Incidence Mortality

Quality of Country Data on
Region/Country Counts Rates Counts Rates Counts Rates Counts Rates Incidence and Mortality
World 1,241,601 34.2 1,098,702 30.0 583,100 13.6 491,223 11.1 —a
Very high HDI 440,520 42.2 371,192 34.1 265,905 21.8 206,330 15.6 —
High HDI 166,118 32.1 148,383 28.6 54,657 8.1 47,284 6.9 —
Medium HDI 607,578 35.6 554,792 32.6 250,192 13.1 226,602 11.7 —
Low HDI 26,870 7.9 23,881 7.1 12,039 3.1 10,738 2.8 —
Northern Africa 11,865 15.6 10,569 14.0 2641 3.1 2371 2.8 —
Eastern Africa 3102 3.8 2809 3.5 2049 2.2 1848 2.0 —
Middle Africa 584 2.0 525 1.8 288 0.8 258 0.7 —
Western Africa 1384 1.7 1225 1.5 992 1.1 860 1.0 —
Southern Africa 4821 26.1 4302 23.8 2588 10.2 2316 9.1 —
Northern America 125,536 44.0 102,415 34.8 114,245 33.8 85,297 23.5 —
Caribbean 5999 25.8 5607 23.7 3542 13.5 3259 12.1 —
Central America 6874 10.2 6180 9.0 3909 4.9 3482 4.3 —
South America 39,452 20.8 35,260 18.4 24,744 10.7 20,814 8.9 —
Eastern Asia 556,089 50.4 501,654 44.8 240,446 19.2 211,141 16.2 —
Southeastern Asia 74,031 29.6 65,763 26.6 30,987 10.5 27,772 9.4 —
South and Central Asia 80,901 11.9 72,969 10.7 24,843 3.4 22,519 3.1 —
Western Asia 31,697 37.6 28,379 34.0 6701 7.1 5854 6.2 —
Western Europe 80,552 44.0 68,063 35.3 39,187 20.0 31,690 14.8 —
Central and Eastern Europe 106,961 53.5 95,692 47.6 31,654 10.4 26,299 8.3 —
Southern Europe 69,933 46.4 61,345 39.1 21,772 12.8 18,288 10.0 —
Northern Europe 33,458 34.6 29,606 29.7 26,703 23.7 22,865 19.1 —
Australia/New Zealand 7811 32.7 5838 23.5 5547 21.7 4053 15.0 —
Melanesia 331 14.3 303 13.3 163 5.8 139 5.0 —
Micronesia/Polynesia 220 42.7 198 38.4 99 17.5 98 17.3 —
Very high HDI
Argentina 7690 32.5 7422 30.9 3554 11.8 3109 10.0 Medium and medium
Australia 6715 33.3 4964 23.6 4616 21.5 3268 14.1 High and high
Canada 13,444 42.5 10,690 32.5 12,037 34.4 9418 25.1 High and high
Germany 34,159 38.8 28,702 31.3 16,654 17.9 14,718 14.5 High and medium
Hungary 5893 76.6 5238 66.6 3395 33.2 2832 26.6 Medium and high
Italy 26,931 38.5 24,686 33.6 10,307 13.2 8845 10.4 Medium and medium
Japan 66,016 38.8 53,752 28.9 28,839 12.9 21,367 8.3 Medium and high
Spain 21,780 52.5 17,430 40.3 4935 11.3 3688 8.0 Medium and medium
Sweden 1928 19.4 1833 17.0 1963 19.1 1862 16.1 High and medium
United Kingdom 21,845 34.9 19,395 30.2 18,537 25.8 16,186 21.4 High and high
United States of America 112,054 44.2 91,693 35.1 102,172 33.7 75,852 23.4 High and high
High HDI
Brazil 20,235 21.3 17,198 17.9 14,045 12.2 11,087 9.5 Medium and medium
China 459,495 52.8 421,695 48.3 193,347 20.4 175,487 18.0 Medium and medium
Iran 3307 10.3 2950 9.1 1581 5.0 1411 4.5 Medium and medium
Mexico 5471 10.5 4945 9.4 2968 4.9 2663 4.3 Medium and medium
Russia 45,599 51.4 41,892 47.1 10,206 6.8 8996 5.6 Medium and medium
Thailand 13,094 30.7 11,854 27.9 6411 12.6 5815 11.6 Medium and medium
Medium HDI
Congo, Republic of 19 1.8 18 1.7 5 0.4 5 0.4 Medium and medium
Egypt 3634 11.2 3245 10.1 1383 3.8 1243 3.4 Medium and medium
Guatemala 369 7.9 333 7.2 278 5.2 251 4.7 Medium and medium
India 53,728 11.0 48,697 9.9 16,547 3.1 15,062 2.9 Medium and medium
Indonesia 25,322 25.8 22,525 23.2 9374 8.1 8379 7.3 Medium and medium
Mongolia 228 27.7 213 26.1 64 5.8 59 5.5 Medium and medium
Nicaragua 179 9.2 162 8.3 116 5.2 106 4.6 Medium and medium
Philippines 8822 31.3 7667 28.2 3252 9.5 2702 8.0 Medium and medium
South Africa 4694 28.7 4187 26.1 2548 11.2 2278 10.0 Medium and medium
(continued)
Table 1. Continued
Males Females
Incidence Mortality Incidence Mortality

Quality of Country Data on
Region/Country Counts Rates Counts Rates Counts Rates Counts Rates Incidence and Mortality
Low HDI
Cameroon 112 2.0 99 1.7 66 1.0 57 0.9 Medium and medium
Kenya 310 3.4 278 3.0 214 2.0 185 1.8 Medium and medium
Zimbabwe 240 7.2 214 6.3 138 3.2 122 2.8 Medium and medium
Note: Rates are age-standardized to the World Standard Population.29,30 Data quality definitions are classified as follows: high-quality incidence refers to
projecting rates to 2012 or applying current rates to the 2012 population AND high-quality national or regional incidence data; medium-quality incidence means
estimated by modeling using either national or regional mortality data, or as the weighted average of local incidence rates OR whenever the data quality and
methods clashed; high-quality mortality refers to projecting rates to 2012 or applying current rates to the 2012 population AND high-quality complete vital
registration data; and medium-quality mortality means estimation of rates AND medium-quality complete vital registration data.
a
Data quality is unavailable for regions.
HDI, Human Development Index.
Data from GLOBOCAN 2012.6
had the highest mortality rate (47.6 in 100,000), fol- United States during 2005–2011, patients in whom lung
lowed by males in Eastern Asia (44.8 in 100,000). The cancer was diagnosed when localized and regional had
highest mortality rates among females were in North moderate 5-year survival rates (55% and 27%, respec-
America (23.5 in 100,000) and Northern Europe (19.1 in tively); however, this rate decreased to 4% for those
100,000). with distant cancer.47 Because of the nonspecific nature
As with incidence, lung cancer mortality rates have of lung cancer symptoms, most lung cancers are typically
changed substantially over time (Fig. 2). For most of the diagnosed after they have advanced (57% of lung can-
included countries (e.g., Australia, Denmark, France, cers in the United States are detected with metastases).47
Germany, Sweden, and the United States), the trends in In England in 2012 almost half (49%) were stage IV
lung cancer mortality closely mirrored those for inci- when diagnosed, two-thirds (69%) were considered
dence, with reductions in mortality among males and advanced (stages III or IV), and only 20% were diag-
increasing or stable trends among females and male-to- nosed when localized (10% were unstaged).48 Stage
female mortality rates converging over time. Parallel proportions can differ by histological type. In the United
and increasing sex-specific mortality trends were States during 2005–2011, SCLCs tended to have the
observed in Romania; mortality rates were stable for both highest proportions of advanced cancers diagnosed
sexes in Japan; and parallel decreasing trends by sex were (almost 90% detected at stages III and IV), with squa-
reported in Hong Kong and the Russian Federation. mous cell cancer having the lowest (approximately
Trends in lung cancer mortality rates for selected coun- 60%).49 In addition, variation in the treatment of lung
tries by sex are listed in Supplementary Table 2. cancer (e.g., time to curative treatment and adherence to
guidelines) is likely an important determinant of the
Survival. Despite the generally poor prognosis, there is differences in survival between countries, even when the
substantial international variation in recently published stage distribution of lung cancer is similar.50,51
5-year relative survival estimates (Table 2). Women tend There have, however, been slight improvements in
to have higher survival of lung cancer than men across lung cancer survival among more socioeconomically
all countries for which estimates by sex are available. developed countries such as Sweden, Japan, the United
These estimates show that Japan had among the highest States, Canada, and Australia during recent decades.31
5-year relative survival worldwide at 30%, whereas The survival rates in Japan are substantially better
Libya, Mongolia, Chile, Bulgaria, and Thailand had among than in other countries, even in the same region. The
the lowest survival rates (<10%). The difference is not explanation for this likely lies in several factors,
solely related to country-specific levels of socioeconomic including a high relative proportion of EGFR mutation–
development, because there is also variation even be- positive lung tumors for targeted therapies, the stan-
tween highly developed countries; for example, the dardized long-term surveillance of lung cancer survivors,
5-year relative survival rate in the United Kingdom is and the coordinated efforts on a national level to
approximately 10%, which is much less than that re- monitor and improve cancer care in Japan.52,53
ported for several other countries with a high HDI. Survival estimates also differ within countries. In
The low survival rate of patients with lung cancer is China during 2005–2009, the 5-year relative survival
related to the stage of lung cancer at diagnosis. In the estimates for lung cancer were considerably higher in
cities such as Beijing (18%) and Haining (23%) than in therapeutic agents or drugs under investigational include
some rural areas such as Qidong (8%) and Jianhu (5%) the following: AKT/serine threonine kinase 1 (AKT1),
(see Table 2). Brazil, Thailand, and Italy also showed at AKT/serine threonine kinase 2 gene (AKT2), BRAF,
least a twofold difference in lung cancer survival rates cyclin-dependent kinase 4 gene (CDK4), echinoderm
between different geographical regions. The reasons for microtubule associated protein like 4 gene–anaplastic
these differences are unclear but may include diagnostic lymphoma receptor tyrosine kinase gene (EML4-ALK),
patterns, because these estimates are not adjusted for erb-b2 receptor tyrosine kinase 2 gene (ERBB2), dicoidin
tumor stage. domain receptor tyrosine kinase 2 gene (DDR2), fibro-
blast growth factor receptor 1 gene (FGFR1), fibroblast
Histological and Molecular Features of Lung Cancer growth factor receptor 3 gene (FGFR3), Harvey rat sar-
The distribution of the histological types/subtypes of coma viral oncogene homolog gene (HRAS), KRAS, KIT
microscopically verified lung cancer varies widely be- proto-oncogene receptor tyrosine kinase gene (KIT),
tween countries (Table 3). Generally among males, the MNNG HOS Transforming gene (MET), neuroblastoma
incidence of adenocarcinoma was higher than that for RAS viral oncogene homolog (NRAS), neurotrophic tyro-
squamous cell carcinoma (adenocarcinoma-to-squamous sine kinase, receptor, type 1 gene (NTRK1),62,63 phos-
cell carcinoma ratio >1). In some countries such as phatidylinositol-4,5-bisphosphate 3-kinase catalytic
Belarus, India, the Netherlands, and the Russian Feder- subunit alpha gene (PIK3CA), platelet derived growth
ation, however, squamous cell carcinoma had the higher factor receptor alpha gene (PDGFRA), ret proto-oncogene
incidence. The pattern of higher incidence of adenocar- (RET), MEK, phosphatase and tensin homolog gene
cinoma compared with squamous cell carcinoma was (PTEN), ROS1, RAS like without CAAX 1 gene (RIT1), and
even more evident among females, with a more than CREB regulated transcription coactivator 1 gene
fivefold difference reported for women in China, Japan, (TORC1).64 The proportions of the genetic events (mu-
and Saudi Arabia. Globally, the incidence of adenocarci- tations, amplifications, or translocations) vary consider-
noma has stabilized in males but continues to increase in ably across published studies and by histologic
females.54 The increase in adenocarcinoma in smokers subtype,65,66 leading to both frequent pathway alter-
has been linked to design changes in cigarettes that have ations (cell cycle regulation and DNA repair) and diver-
promoted deeper inhalation since the late 1950s.12,55 gent effects (RAS/RAf, mammalian target of rapamycin,
Studies in Southeast Asia, where prevalence of smoking and Jak-STAT in adenocarcinoma versus squamous dif-
among females is low, have suggested that the rise of ferentiation, oxidative stress and PIK3CA in squamous
adenocarcinoma in females can be attributed to cell carcinoma). Supplementary Figure 1 summarizes the
secondhand smoke and cooking fumes.56–58 difference in the distribution of mutations in adenocar-
For those countries for which histology-specific sur- cinoma in a Chinese population67 and in the U.S. and
vival data were available (Australia and the United States European populations.68–70 In East Asia, where the
[Table 4]), the 5-year relative survival was higher for burden of EGFR mutations is much higher in adenocar-
adenocarcinoma and squamous cell carcinoma than for cinoma than in the United States and Europe, the fre-
either large cell carcinoma or SCLC. In the United States, quencies of other mutations are also different. In
blacks, primarily males,59,60 have lower survival rates for comparisons described by Kohno et al.70 and Li et al.,64
adenocarcinoma and squamous cell carcinoma than do ERBB2, RET, BRAF and ROS1 mutations frequencies in
whites and other racial/ethnic groups. adenocarcinoma are essentially the same in East Asian
At the molecular level, identifying somatic mutations and white populations whereas there are significantly
in the lung is important, as current treatment strategies more KRAS mutations in the white population (20%–
rely heavily on these markers to identify the patients who 30% versus 8%–10%, respectively). In a pooled analysis
would benefit the most from targeted therapies.61 to describe the spectrum of somatic mutations in African
Currently, the genes for which standard genetic aberra- Americans, although the frequencies of EGFR and KRAS
tions are evaluated and for which there are approved mutations are comparable, African Americans have a
Figure 1. Trends in lung cancer incidence rate by country, 1980–2011. (A) Increasing trend in both sexes. (B) Rates in males increase but
rates in females are relatively stable. (C) A stable trend in both sexes. (D) Rates in males are relatively stable but those in females are
decreasing. (E) Rates in males decrease whereas rates in females increase. (F) A decreasing trend in both sexes. The y axis represents
incidence rate per 100,000 population per year and is on the log scale; the x axis represents year. Incidence rates have been age-
standardized to the World Standard Population.29,30 Trends have been calculated using Joinpoint software, version 4.0.4 (National
Cancer Institute). Countries are grouped by their most recent trend. Data from Australian Institute of Health and Welfare (Australia),19
Hong Kong Cancer Registry (Hong Kong),24 National Cancer Registry Ireland (Ireland),20 National Cancer Center (Japan),21 Netherlands
Comprehensive Cancer Organisation (Netherlands),22 National Board of Health and Welfare (Sweden),23 Surveillance, Epidemiology, and
End Results-9 (United States),25 and International Agency for Research on Cancer (all other countries).18
mutational pattern distinct from that of white Americans, Nonetheless, despite the high mortality-to–incidence
with a significantly higher proportion of unknown driver rate ratios, lung cancer continues to carry a compara-
mutations that are not yet fully characterized (77% of tively small burden of overall mortality in most of this
NSCLCs and 70% of non–squamous cell lung cancers).71 region, especially compared with communicable diseases
The frequency of mutations in squamous cell carci- such as human immunodeficiency virus/acquired im-
noma, without mixed histologic features, is summarized in munodeficiency syndrome.77–80
Supplemental Figure 2.72 In addition to these distinct The prevalence of smoking among African men is
mutations, as with adenocarcinoma, there are other fivefold to 10-fold higher than among African women. In
frequently amplified genes that are also actionable, either 2012, approximately half (45%) of men in Tunisia were
directly or indirectly, including FGFR1 (20%), SRY (sex identified as smokers (compared with 4.5% of women),
determining region Y)-box 2 (SOX2) (20%), MDM2 proto- and in Nigeria the percentages were 7.5% in men and
oncogene, E3 ubiquitin protein ligase gene (MDM2) 1.4% in women.43 In countries of the Sub-Saharan region
(10%), MET (6%), and PDGFRA (8%–10%). The difference (Benin, Malawi, Mozambique, Niger, Sierra Leone, and
in mutational spectrum seen between adenocarcinoma Swaziland), the prevalence of current smoking in males
and squamous cell carcinoma illustrates how the treat- ranged from 8.7% to 34.6% during 2003–2009, which is
ment for NSCLC treatment has evolved into a histology- expected to drive an increase in lung cancer mortality in
based subtyping approach targeting the mutations in the next decade.81
adenocarcinoma versus in squamous cell carcinoma.64,73
Central and South America. In most countries, mor-
Region- and Country-Specific Profiles tality rates in males have been decreasing since the
Africa. Incidence rates of lung cancer remain low across 1980s or 1990s, but among females, the rates have been
most of Africa, which has the lowest incidence rates in steadily increasing.82–84 In 2012, although most coun-
males of all the continents (7.7 in 100,000), with lung tries had incidence rates less than 25.0 in 100,000 and
cancer mortality rates of 7.0 in 100,000.6 Because the mortality rates less than 20.0 in 100,000 among males,
risk of lung cancer increases exponentially in late-middle there were some notable exceptions, including the esti-
and older age, the low incidence rate may in part result mated incidence in Uruguay (50.6 in 100,000), Cuba
from the generally lower life expectancy in Africa (42.8 in 100,000), and Argentina (32.5 in 100,000).6 Of
compared with on other continents.74 In general, the these, Cuba had incidence and mortality rates
lowest incidence rates for lung cancer are reported for approaching those in North America for both men (42.8
western, middle, and eastern Africa, whereas the highest and 39.6 in 100,000, respectively) and women (23.8 and
rates are found in southern and northern Africa (see 21.6 in 100,000, respectively).6 The incidence of lung
Table 1). Within Africa, Réunion (32.3 in 100,000) and cancer in these countries may be largely attributable to
Tunisia (31.1 in 100,000) had the highest lung cancer their previously high smoking rates—38.7% and 23.7%
incidence rates in males, whereas Niger (0.4 in 100,000) in Uruguay, 30.8% and 15.3% in Cuba, and 30.8% and
had the lowest.6 22.5% in Argentina for men and women, respectively, in
The average rates of incidence and mortality from 1980.43 Since then, the smoking prevalence rates in
lung cancer are substantially lower among women, at 2.6 these countries, as well as in several South American
and 2.4 in 100,000, respectively; however, the rate var- countries, including Chile, Bolivia, and Brazil, have been
ies across countries, with females in South Africa having progressively decreasing for both sexes.43 In females, the
much higher incidence rates (11.2 in 100,000) than in impact of decreasing smoking prevalence may not yet
other African countries. This observation is potentially have been manifested in trends in lung cancer incidence.
due to the higher prevalence of smoking among females
in South Africa (10.4% in 1980 and 9.1% in 2012) Australia. Projected estimates of cancer incidence in
compared with in other African countries in general.43,75 2014 in Australia indicate that lung cancer was the fourth
Many African countries have poor data coverage and most frequently diagnosed cancer (excluding keratino-
quality, and it has been suggested that incidence and cyte carcinoma) among males (10% of all cancers) and
mortality rates may be higher than these estimates.76 females (8% of all cancers), but the number 1 cause of
Figure 2. Trends in lung cancer mortality rate by country, 1980–2012. (A) An increasing trend in both sexes. (B) Rates in males
are relatively stable but rates in females are increasing. (C) Rates in males decrease whereas those in females increase. (D)
Rates in males decrease whereas those in females are relatively stable. (E) A decreasing trend in both sexes. The y axis rep-
resents mortality rate per 100,000 population per year and is on the log scale; the x axis represents year. Mortality rates have
been age-standardized to the World Standard Population.29,30 Trends have been calculated using Joinpoint software, version
4.0.4 (National Cancer Institute, Bethesda, MD). Countries are grouped by their most recent trend. Data from WHO.26
Table 2. Five-Year Net Survival (%) Estimates of Lung decreased among Australian men since 1982, with the
Cancer in Selected Countries and Groups mortality reduction more pronounced since 1989. Among
women, incidence rates have increased since 1982,
5-Year Net Survival (%) (95% CI)
whereas mortality rates increased sharply to 1991, after
Country Period Total Males Females which the rate of increase leveled off to the 2011 rate (see
Algeria 2005–2009 15 (11–18) — a
— Figs. 1 and 2 and Supplementary Tables 1 and 2).
Argentina 2005–2009 12 (10–14) — — Approximately three-quarters of Australian men
Australia 2006–2010 14 (14–14) 13 (12–13) 17 (16–17) were reported to be smokers at the end of World War II,
Brazil 2005–2009 18 (13–23) — — along with approximately one-fourth of Australian
Aracaju 2005–2009 19 (12–25) — — women. The prevalence of male adult smokers decreased
Jahu 2005–2009 9 (4–14) — —
from then onward, down to 43% in 1976 and 22% in
Bulgaria 2005–2009 6 (6–7) — —
Chile 2005–2009 6 (2–10) — — 2010.86–88 Among female adults, however, smoking
China 2005–2009 18 (17–18) — — prevalence increased to 33% in 1976 and then
Beijing 2005–2009 18 (18–19) — — decreased steadily to 18% in 2010.86–88
Cixian 2005–2009 19 (14–24) — — Several authors89,90 have suggested that the decline
Haining 2005–2009 23 (20–25) — — in smoking prevalence during the 1980s and 1990s in
Jianhu 2005–2009 5 (2–8) — —
Australia was correlated with the level of Australian
Qidong 2005–2009 8 (6–10) — —
Colombia 2005–2009 9 (7–11) — —
tobacco control activities during that time. After the
Denmark 2009–2013 — 11 (11–12) 16 (15–17) release of the Surgeon General’s report in 1964,91 there
Finland 2009–2013 — 10 (10–11) 16 (15–17) was a gradually increasing awareness in Australia of the
Germany 2005–2009 16 (16–17) — — harm caused by smoking. Since then, Australia has
Iceland 2009–2013 — 14 (11–18) 20 (17–24) become a world leader in tobacco control, with some of
India 2005–2009 10 (5–15) — — the strongest legislation in the world, including being the
Indonesia 2005–2009 12 (1–23) — —
first to introduce tobacco plain packaging in 2012.92
Italy 2005–2009 15 (14–15) — —
Biella 2005–2009 8 (5–11) — —
After the WHO Framework Convention on Tobacco
Milano 2005–2009 17 (15–19) — — Control,93 Australia has progressively raised the tax on
Romagna 2005–2009 19 (17–20) — — cigarettes; made public spaces, eating and drinking
Japan 2005–2009 30 (29–31) — — areas, and other enclosed areas smoke free; subsidized
Libya (Benghazi)b 1995–2009 2 (1–4) — — methods to quit smoking; and consistently run education
Mongoliab 1995–2009 7 (4–9) — —
and prevention campaigns.87
Norway 2009–2013 — 15 (14–15) 19 (18–20)
Saudi Arabia 2005–2009 13 (7–19)
Indigenous Australians were reported to have nearly
Sweden 2009–2013 — 14 (13–15) 19 (18–19 ) a twofold higher risk of receiving a diagnosis of lung
Thailand 2005–2009 8 (7–9) — — cancer than nonindigenous Australians between 2005
Khon Kaen 2005–2009 14 (10–17) — — and 2009, making lung cancer the most frequent cancer
Lampang 2005–2009 6 (5–8) — — diagnosed among Indigenous Australians, with a similar
Songkhla 2005–2009 7 (5–9) — — differential for lung cancer mortality.85 In addition,
Tunisia 2005–2009 10 (0–21) — —
Australians living in the most disadvantaged areas of the
Turkey 2005–2009 10 (9–11) — —
United Kingdom 2005–2009 10 (9–10) — —
country had significantly higher lung cancer incidence
United States 2010 15 (15–15) 13 (13–13) 18 (18–18) and mortality rates than did those living in more affluent
White 2010 15 (15–16) 13 (13–13) 18 (18–18) areas.85 The inequalities by indigenous status and area
Black 2010 13 (13–13) 11 (11–11) 15 (15–16) disadvantage are both consistent with the higher re-
Otherc 2010 16 (16–16) 14 (14–14) 19 (19–20) ported smoking prevalence in these subgroups.85
Note: No total estimates were available from NORDCAN. Italic means that
estimates are of lower quality.
a
Data were unavailable. China. It is estimated that more than one of every three
b
c
For Libya and Mongolia, estimates were not available for 2005–2009. lung cancers occurs in China (36% of the world total [see
American Indian/Alaska Native or Asian/Pacific Islander.
CI, confidence interval.
Table 1]). In the past four decades in China, lung cancer
Data from Australian Institute of Health and Welfare (Australia),34 NORDCAN has surpassed other major cancers to become the lead-
(Nordic countries),32 Surveillance, Epidemiology, and End Results-18 (the ing cause of cancer deaths for both men and women.94
United States),33 and the CONCORD-2 study (all others).31
Lung cancer incidence has steadily increased from
1988 to 2011.94–99 Cancer registry coverage in China has
cancer death for both men and women.85 Lung cancer been improving and is now coordinated by the National
mortality accounts for approximately one-fifth of all Center Cancer Registry. In 2011, the data from 177
cancer deaths (20% in men and 18% in women). Inci- cancer registries covering more than 175 million (13%)
dence and mortality rates of lung cancer have steadily of the total Chinese population showed that the
Table 3. Incidence Rates (per 100,000) of Microscopically Verified Lung Cancer by Histological Type
Males Females
Country or Area of Registry/Ethnicity SCC AC LCC SCLC AC/SCC Ratio SCC AC LCC SCLC AC/SCC Ratio
Australia 6.7 9.5 4.7 3.8 1.4 0.6 0.4 0.3 0.0 0.7
Belgium 19.2 18.4 3.8 9.0 1.0 2.8 8.0 1.0 3.0 2.9
Belarus 26.9 5.8 1.7 6.4 0.2 1.1 1.4 0.1 0.3 1.3
Brazil 4.1 5.9 3.9 1.4 1.4 1.2 3.1 1.6 0.8 2.8
Canada 9.5 11.9 3.7 5.0 1.3 3.9 11.8 2.5 4.0 3.0
Chinaa,b 6.5 9.3 1.3 2.6 1.4 1.1 7.1 0.6 0.6 6.6
China, Beijing City 8.3 9.4 2.2 3.8 1.1 1.7 8.6 1.2 1.2 5.1
China, Nangang District, Harbin City 2.2 1.2 — 1.2 0.5 0.4 0.8 — 0.3 2.0
China, Shanghai City 6.3 8.2 0.2 1.4 1.3 0.7 7.1 0.1 0.2 10.1
China, Cixian County 15.4 20.7 — 3.5 1.3 7.1 9.5 — 1.1 1.3
China, Hong Kong 9.9 19.1 1.5 4.5 1.9 1.3 12.6 0.5 0.6 9.7
Egypt, Gharbiah 2.2 2.9 3.0 1.4 1.3 0.3 1.5 0.7 0.2 5.0
Indiac 1.6 1.4 2.1 1.0 0.9 0.4 0.8 0.7 0.3 2.1
India, Bangalore 0.9 1.8 2.0 0.7 2.0 0.2 0.8 0.8 0.2 4.0
India, Chennai 2.2 1.9 2.4 0.5 0.9 0.3 0.8 0.7 0.1 2.7
India, Mumbai 1.4 2.2 0.7 1.3 1.6 0.3 1.1 0.2 0.4 3.7
India, New Delhi 1.8 0.8 4.4 1.1 0.4 0.3 0.4 1.1 0.2 1.3
Japan 9.1 14.9 1.8 4.3 1.6 1.0 8.7 0.3 0.7 8.7
The Netherlands 13.3 11.8 8.3 7.3 0.9 3.5 8.1 4.3 4.8 2.3
Russiaa 15.6 4.0 1.6 4.7 0.3 1.3 1.4 0.2 0.6 1.1
Saudi Arabia 1.1 2.2 0.7 0.6 2.1 0.2 1.3 0.0 0.0 6.2
Sweden 5.1 7.1 4.5 2.5 1.4 2.5 7.6 3.4 2.2 3.0
Tunisia, North 7.8 4.9 8.2 3.8 0.6 0.4 0.6 0.8 0.2 1.5
Thailanda 3.6 8.1 2.1 1.5 2.2 1.1 4.4 0.9 0.5 4.0
Uruguay 8.6 8.5 5.8 3.4 1.0 1.1 2.5 1.0 0.8 2.3
United States
United States, American Indian 8.9 7.9 1.9 4.8 0.9 4.6 7.6 1.2 4.9 1.7
United States, Asian and Pacific Islander 4.3 10.3 1.5 2.3 2.4 1.3 8.4 0.8 0.9 6.5
United States, black 15.8 18.4 4.2 6.0 1.2 5.8 11.8 1.9 3.9 2.0
United States, white 11.6 14.3 2.9 7.0 1.2 5.4 12.6 1.8 6.0 2.3
Note: Rates are age-standardized to the World Standard Population.29,30 Italicized names indicate that less than 60% of cases were microscopically verified.
a
Exact percentages of microscopically verified cases were 59.1%, 55.4% and 54.7% for China, Russia, and Thailand, respectively.
b
China includes data from the 14 available cancer registries in China.
c
India includes data from the 12 available cancer registries in India.
SCC, squamous cell carcinoma; AC, adenocarcinoma; LCC, large cell carcinoma.
Data from Cancer Incidence in Five Continents Volume X (2003–2007).15
incidence of lung cancer was 48 in 100,000 in men and politics and culture, with the tobacco industry in China
22 in 100,000 in women,97 and these numbers are being nationally monopolized and an important source
similar to the GLOBOCAN estimates (see Table 1). Inci- of tax revenue.104 For example, as etiquette, cigarettes
dence of lung cancer and mortality were generally higher are commonly offered to guests, even by nonsmokers.105
in urban areas and eastern China than in rural areas and The prevalence of smoking among physicians remains
western China.98,99 substantial (>50% of male physicians in many cities and
Similarly to in Western countries, the proportion of provinces).106,107 Thus, awareness of the health hazards
adenocarcinoma among male patients with lung cancer of smoking remains poor and tobacco control policies
has increased to a level similar to or higher than that of face many barriers and challenges in China.108,109
squamous cell carcinoma (see Table 3).100 Lung cancers Given that the prevalence of smoking among women
in females are predominately adenocarcinoma.101 in China has historically been very low (and is
The rise of tobacco use among Chinese males decreasing) (5% in 1980 and 2% in 2012),43,110 expo-
(average consumption of one cigarette per day in 1952 sure to risk factors other than active smoking may play
and 10 cigarettes per day in 1992) has been the major an important role in the incidence of lung cancer in fe-
determinant of male lung cancer incidence.102,103 One- males. Exposure to secondhand smoke and indoor and
third of the world’s tobacco is grown and consumed in outdoor air pollution remain common in China.99 Large-
China.104 Cigarette smoking has a unique role in Chinese scale surveys showed that 83% to 95% of adults
Table 4. Five-Year Relative Survival by Histological Subtype in Australia and the United States
Histological Subtype
Squamous Cell Large Cell

Carcinoma Adenocarcinoma Carcinoma SCLC
Country RS (%) (95% CI) RS (%) (95% CI) RS (%) (95% CI) RS (%) (95% CI)
Australia 18.2 (17.2–19.3) 19.7 (18.8–20.5) 8.3 (7.6–9.1) 6.6 (5.9–7.4)
United States 17.2 (17.0–17.4) 21.4 (21.2–21.5) 8.0 (7.9–8.2) 6.3 (6.2–6.5)
United States by race
White 17.9 (17.6–18.1) 21.8 (21.6–22.1) 7.9 (7.8–8.1) 6.3 (6.2–6.5)
Black 13.2 (12.7–13.8) 16.9 (16.4–17.4) 8.1 (7.6–8.6) 5.8 (5.3–6.4)
Other 15.5 (14.5–16.4) 21.9 (21.2–22.6) 8.7 (7.9–9.4) 6.9 (6.1–7.7)
RS, relative survival; CI, confidence interval.
Data from the Australian Institute of Health and Welfare (Australia, 2006–2010)34 and Surveillance, Epidemiology, and End Results-18 (the United States,
2010).33
reported secondhand smoke in restaurants; 53% to 84% respectively, in California versus 125.9 and 80.3 in
reported exposure at their workplace; and 40% of those 100,000 for males and females, respectively, in Ken-
who lived with smokers reported exposure at tucky; adult smoking prevalence 14% in California
home.111,112 The smoking ban or tobacco-free policy in versus 30% in Kentucky).121,122 For lung cancer mor-
public places often fails to protect nonsmokers from tality, the rate declined continuously from 1973 to 2007
exposure because of lack of enforcement.112 In addition, among white women in California, but not among those
women in rural areas in particular are exposed to fumes in several southern and midwestern states.123 The
and smoke produced while cooking with biomass fuels geographical variation results mainly from different de-
such as coal and wood,113 and people in major cities grees of tobacco control measures between these states.
often face hazardous levels of air pollution.114 In addition to the sex and geographical differences,
Although it has been suggested that cigarette smok- lung cancer incidence varies by histological and racial
ing may cause more lung cancer in urban versus rural groups. Whereas squamous cell carcinoma and SCLC
areas in China,115 the extent to which these different rates are declining, the incidence of adenocarcinoma
sources and levels of exposure contribute to the continues to increase among every racial and sex group.3
observed urban-rural differential in lung cancer inci- What is more alarming is that in younger cohorts, the
dence and histological features warrants further study. incidence of adenocarcinoma in females has surpassed
that in males.3 African American males have a higher
United States. Lung cancer is the second most frequent incidence of both adenocarcinoma and squamous cell
cancer (accounting for 14% of cancers diagnosed among carcinoma than do white males. The difference remains
both males and females), and it is the number 1 cause of given the same amount of smoking exposure.124
cancer deaths for both sexes. Lung cancer mortality ac- Whereas African American smokers frequently
counts for more than a quarter of all cancer deaths (29% preferred menthol cigarettes, evidence suggests that
in men and 26% in women).116 Chronologically, the menthol cigarettes alone cannot explain the racial
epidemic of lung cancer in the United States aligns with disparity in incidence of lung cancer.125–130 In addition,
historical patterns of tobacco use. The annual cigarette the incidence of lung cancer in Asian Americans, who
consumption per capita for persons aged 18 years or had a lower prevalence of smoking, is overall lower than
older increased by more than 70 times (from 54 to in whites.131 However, given the same amount of
4,000) from 1880 to the 1970s.117 Lung cancer mortality smoking, lung cancer may be more likely to develop in
in men increased 18-fold (from five to 90 in 100,000) Asian Americans than in whites.132 Risk factors other
between 1930 and 1990.116 On the basis of our trend than cigarette smoke or biological factors may be
analysis, incidence and mortality rates have started to responsible for these racial differences.
decline for men since the 1990s and women’s rates have
also leveled off since early 2000 and started to show
signs of decrease since 2010,3,35 mainly thanks to a Opportunities to Reduce the Burden of Lung
decrease in smoking prevalence.118–120 Cancer
Geographically, lung cancer incidence is also highly Prevention. As noted already, the major key driver of
associated with smoking prevalence (lung cancer inci- trends in lung cancer incidence is smoking.36 Because of
dence 60.4 and 44.4 in 100,000 for males and females, the limited efficacy of high-cost screening and treatment
measures, smoking is also a key driver of lung cancer to remain an important cost-effective approach to
mortality.133 For this reason, effective tobacco control increasing survival.152,153
programs are critically important in the battle to reduce
the burden of lung cancer internationally, even more so New Treatments. Surgical resection continues to be the
within African and Central and South American countries most effective treatment for localized tumors, although
that have very limited access to screening and treatment this relies on lung cancer being diagnosed at an early
measures.81 Populations that have benefited from stage and at present, only a small proportion of lung
decreasing smoking prevalence because of coordinated cancers meet this criterion.154 Some recent advances
tobacco control programs, such as in Australia,87 Cali- involving novel, minimally invasive surgical and radio-
fornia in the United States,134 and Hong Kong,135 are therapy approaches have been made in the management
likely to experience continued reductions in lung cancer of early-stage NSCLC, whereas the introduction of
incidence, particularly among males, over the coming platinum-based chemotherapy has been shown to pro-
years. Rates of lung cancer in females are expected to vide a survival benefit for metastatic NSCLC.155 In
rise continuously in many countries with a very high addition, genetic testing, which screens actionable ge-
HDI,136–138 although there is evidence of a decline in netic alterations (including EGFR mutations) for targeted
other places, such as the United States.3,35 Given the lag therapy,156 will likely provide important information
period between smoking prevalence and resultant dis- about the treatment and prognosis of lung cancer,
ease, it is almost certain that countries without strong although the treatment affects only a small minority of
antitobacco programs, such as China, will face an patients with lung cancer overall. Beyond the approved
increasing burden of lung cancer in upcoming de- therapies aimed at EGFR, including tyrosine kinase in-
cades.139 A comprehensive lung cancer control policy hibitors such as gefitinib, erlotinib, and afatinib,157 many
would also incorporate coordinated strategies to reduce small molecules are in various phase trials to target
exposure to other recognized risk factors, including EGFR. Most of the mutations, fusions, or amplifications
secondhand smoke, air pollution, radon, asbestos, and are being tested in phase I, II, or III clinical trials.
occupational carcinogens.140–142 Guidelines for determining which patients with lung
cancer should have molecular testing were summarized
Early Detection. Limited options exist to detect lung in 2013 by Lindeman et al.158 The final recommenda-
cancer at an early stage, and recent development of tions, which are summarized and graded on the basis of
screening tools, such as sputum and plasma-based the evidence in the literature, suggest that all patients
microRNA,143,144 still require multicenter clinical trials with advanced-stage lung cancer, regardless of age, sex,
for further validation.145 However, screening for lung smoking exposure, or other clinical factors, should have
cancer with low-dose computed tomography in high- molecular testing with tissue priority given to EFGR and
risk populations, which has been demonstrated to anaplastic lymphoma receptor tyrosine kinase testing.
reduce mortality by 20%,146,147 has started to receive From 2013 to today, the rates of testing across the globe
approval by major insurers in the United States since have remained variable. In China, for example, survey
2015. In countries that can afford to implement data showed that only 9.6% of cases of NSCLC were
screening in a large proportion of high-risk populations, tested for EGFR mutation,159 whereas in Sweden, 49%
it is expected that incidence of lung cancer, including a of cases received testing. With the ever-growing list of
higher proportion of early-stage lung cancer, may in- actionable mutations, improved sampling and analysis of
crease whereas mortality may decrease because of the scarce tissue with ever-advancing high-throughput
survival advantages of early-stage cancers. These technologies (e.g., next-generation sequencing)160 will be
changes may also vary among racial/ethnic groups, as required to support the use of these tests to direct the
race-related factors such as socioeconomic status and development of new agents and improve clinical care
educational attainment can affect the accessibility of and outcomes.73,157
and willingness to receive cancer screening.148,149 Further, immunotherapy appears set to offer new
However, the widespread implementation of low-dose modes of treatment for NSCLC, even for patients with
computed tomography screening will likely be advanced disease, building on progress in the un-
restricted to countries with the financial means to pay derstanding of antitumour immune responses.161
for these tests.150 Thus, to make a global impact on Corresponding gains are yet to be realized in the
reducing lung cancer mortality rates, tobacco control to treatment of SCLC, with limited options because of
prevent the uptake of smoking remains the single most barriers in the development molecular profiling
important factor.151 For those who already smoke, leading to the use of targeted agents; work in this
smoking cessation before or after diagnosis is expected field is continuing.162,163
Limitations among men and women—United States, 2005-2009.

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ORIGINAL ARTICLE

The International Epidemiology of Lung Cancer:

Received 13 July 2015; revised 13 May 2016; accepted 26 May 2016

ABSTRACT 2016 International Association for the Study of Lung

Journal of Thoracic Oncology Vol. 11 No. 10: 1653-1671

Incidence Mortality Incidence Mortality

Incidence Mortality Incidence Mortality

Squamous Cell Large Cell

Limitations among men and women—United States, 2005-2009.

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